Pharmacologically active compounds

ABSTRACT

The compounds are substituted S-(aminoalkyl)-isothioureas which are histamine H 2  -antagonists. Two specific compounds of the present invention are S-[6-(N&#39;-methylthioureido)hexyl]isothiourea and S-[5-(N&#39;-cyano-N&#34;-methylguanidino)pentyl]isothiourea.

This invention relates to pharmacologically active compounds, to methodsfor preparing these compounds, to pharmaceutical compositions containingthese compounds and to methods of blocking histamine H₂ -receptors byadministering these compounds. The compounds of the invention willnormally exist as acid addition salts and hydrated salts but, forconvenience reference will be made throughout this specification to theparent compounds.

Many physiologically active substances elicit their biological actionsby interaction with specific sites known as receptors. Histamine is sucha substance and has a number of biological actions. Those biologicalactions of histamine which are inhibited by drugs commonly called"antihistamines" of which mepyramine, diphenhydramine andchlorpheniramine are typical examples are mediated through histamine H₁-receptors (Ash and Schild, Brit. J. Pharmac. Chemother., 27, 427,(1966)). However, other of the biological actions of histamine are notinhibited by "antihistamines" and actions of this type which areinhibited by a compound described by Black et al. (Nature, 236, 385,(1972)) and called burimamide are mediated through receptors which aredefined by Black et al. as histamine H₂ -receptors. Thus histamine H₂-receptors may be defined as those histamine receptors which are notblocked by mepyramine but are blocked by burimamide. Compounds whichblock histamine H₂ -receptors are referred to as histamine H₂-antagonists.

Blockade of histamine H₂ -receptors is of utility in inhibiting thebiological actions of histamine which are not inhibited by"antihistamines". Histamine H₂ -antagonists are therefore useful, forexample, as inhibitors of gastric acid secretion, as anti-inflammatoryagents and as agents which act on the cardiovascular system, for exampleas inhibitors of the effects of histamine on blood pressure. In thetreatment of certain conditions, for example inflammation and inhibitingthe actions of histamine on blood pressure, a combination of H₁ - and H₂-antagonists is useful.

The compounds of this invention are histamine H₂ -antagonists. Thesecompounds are represented by the following Formula 1: ##STR1## wherein nis an integer from 3 to 6; R is lower alkyl or ##STR2## and X issulphur, NCN or CHNO₂, or a pharmaceutically acceptable acid additionsalt thereof. It will be understood that the structure illustrated inFormula 1 is only one of several possible representations and that othertautomeric forms are also covered by the present invention. Throughoutthe present specification by the term "lower alkyl" we mean an alkylgroup containing from 1 to 4 carbon atoms.

Preferably X is sulphur or NCN, and particularly preferably NCN.

Particularly useful compounds are those wherein n is 5 or 6. Specificuseful compounds falling within the scope of the invention include:

S-[6-(N'-methylthioureido)hexyl]isothiourea

S-[5-(N'-methylthioureido)pentyl]isothiourea

S-[5-(N'-cyano-N"-methylguanidino)pentyl]isothiourea and

S-[6-(N'-cyano-N"-methylguanidino)hexyl]isothiourea

The compounds of Formula 1 may be prepared by treating a compound ofFormula 2 ##STR3## wherein n and X are as defined in Formula 1, R² islower alkyl or --(CH₂)_(n) A, A is chlorine, bromine, iodine,p-toluenesulphonyloxy, methanesulphonyloxy or other suitable groupdisplaceable by sulphur, R' is hydrogen when X is NCN or CHNO₂, and R'is a suitable thiourea protecting group when X is sulphur, withthiourea, and when X is sulphur subsequent removal of the protectinggroups R'. Preferably the reaction with thiourea is carried out underessentially anhydrous conditions. Preferably the reaction with thioureais carried out in the presence of a suitable inert solvent, e.g.acetone, at an elevated temperature e.g. 50° to 150°. Preferred thioureaprotecting groups are those where ##STR4## forms a2-thioxo-4,5-imidazolidinedione or a a 5,5-dialkyl-2-thiobarbituratering. These protecting groups may be removed under mildly basicconditions, e.g. treatment with ammonium hydroxide in an aqueousalcohol, and the 5,5-dialkyl-2-thiobarbiturate ring can also be cleavedby refluxing in an aqueous alcohol in the presence of an acid.

The starting materials of Formula 2 wherein X is NCN or CHNO₂ and R² islower alkyl may be prepared according to the scheme: ##STR5## InFormulas 4, 5 and 6 Alk represents lower alkyl. A compound of Formula 4,wherein X is NCN or CHNO₂, may be reacted with an aminoalkanol ofFormula 3 to give a compound of Formula 5, which may be converted into acompound of Formula 6 by standard methods, e.g. treatment withp-toluenesulphonyl chloride in pyridine. An alternative method forpreparing the compounds of Formula 4 is to treat dimethylN-cyanodithioimidocarbonate or 1-nitro-2,2-bis(methylthio)ethylene firstwith one equivalent of an amine of Formula 3, and then with an excess ofa lower alkylamine.

The starting materials of Formula 2 wherein X is NCN or CHNO₂ and R² is--(CH₂)_(n) A may be prepared by treating dimethylN-cyanodithioimidocarbonate or 1-nitro-2,2-bis(methylthio)ethylene withat least two equivalents of an amine of Formula 3, to give a compound ofFormula 7. Compounds of Formula 7 ##STR6## may be converted intocompounds of Formula 8 e.g. by treatment with p-toluenesulphonylchloride in pyridine.

The starting materials of Formula 2 wherein X is sulphur and both thegroups R' form part of a 2-thioxo-4,5-imidazolidinedione ring may beprepared according to the scheme: ##STR7## A compound of Formula 9wherein R³ is hydrogen or lower alkyl, is treated with oxalyl chlorideto give a compound of Formula 10 which is then treated under anhydrousbasic conditions with a compound of formula A(CH₂)_(n) A where n and Aare as defined in Formula 1 to give a compound of Formula 11, or acompound of Formula 12 where Alk is lower alkyl. It will be apparentthat at least two molar equivalents of the compound A(CH₂)_(n) A shouldbe used to prepare a compound of Formula 11 from a compound of Formula10 wherein R³ is hydrogen.

Compounds of formula 2 wherein both the groups R' form part of a5,5-dialkyl-2-thiobarbiturate ring may be prepared by treating acompound of Formula 9 with a diethyl 2,2-dialkylmalonate, followed byreactions analogous to those outlined immediately above.

The compounds of Formula 1 block histamine H₂ -receptors, that is theyinhibit the biological actions of histamine which are not inhibited by"antihistamines" such as mepyramine but are inhibited by burimamide. Forexample, the compounds of this invention have been found to inhibithistamine-stimulated secretion of gastric acid from the lumen-perfusedstomachs of rats anaesthetised with urethane, at doses of from 0.5 to256 micromoles per kilogram intravenously. This procedure is referred toin the above mentioned paper of Ash and Schild. The activity of thesecompounds as histamine H₂ -antagonists is also demonstrated by theirability to inhibit other actions of histamine which, according to theabove mentioned paper of Ash and Schild, are not mediated by histamineH₁ -receptors. For example, they inhibit the actions of histamine on theisolated guinea pig atrium and isolated rat uterus.

The compounds of this invention inhibit the basal secretion of gastricacid and also that stimulated by pentagastrin or by food.

In addition, the compounds of this invention show anti-inflammatoryactivity in conventional tests such as the rat paw oedema or theguinea-pig U.V. erythema tests. In the former the oedema is induced byan irritant, and in the latter the depilated skin of the guinea-pig isexposed to U.V. radiation and an erythema results. Subcutaneousinjection of doses of a compound of Formula I reduces the rat paw volumein the former test and reduces the intensity of the guinea-pig erythemain the latter test.

A useful modification of the guinea-pig U.V. erythema test is toirradiate only the whole ear and measure the ear temperature by athermistor probe. Subcutaneous injection of doses of about 0.1 mmol/kgof a compound of Formula 1 to a guinea-pig reduces the rise in eartemperature caused by U.V. irradiation.

The level of activity of the compounds of this invention is illustratedby the effective dose producing 50% inhibition of gastric acid secretionin the anaesthetised rat and the dose producing 50% inhibition ofhistamine-induced tachycardia in the isolated guinea-pig atrium.

For therapeutic use, the pharmacologically active compounds of thepresent invention will normally be administered as a pharmaceuticalcomposition comprising as the or an essential active ingredient at leastone such compound in the form of an addition salt with apharmaceutically acceptable acid and in association with apharmaceutical carrier therefor. Such addition salts include those withhydrochloric, hydrobromic, hydriodic, sulphuric, acetic and maleic acidsand may conveniently be formed by standard procedures, for example bythe use of ion-exchange resins to form the required salt.

Pharmaceutical compositions comprising a pharmaceutical carrier and apharmaceutically acceptable acid addition salt of a compound of Formula1 and methods of blocking histamine H₂ -receptors which compriseadministering this salt to an animal are also objections of thisinvention. The pharmaceutical carrier employed may be, for example,either a solid or liquid. Exemplary of solid carriers are lactose, terraalba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate,stearic acid and the like. Exemplary of liquid carriers are syrup,peanut oil, olive oil, water and the like.

A wide variety of pharmaceutical forms can be employed. Thus, if a solidcarrier is used, the preparation can be tableted, placed in a hardgelatin capsule in powder or pellet form, or in the form of a troche orlozenge. The amount of solid carrier will vary widely but preferablywill be from about 25 mg to about 500 mg. If a liquid carrier is used,the preparation may be in the form of a syrup, emulsion, soft gelatincapsule, sterile injectable liquid contained for example in an ampoule,or an aqueous or nonaqueous liquid suspension.

The pharmaceutical compositions are prepared by conventional techniquesinvolving procedures such as mixing, granulating and compressing ordissolving the ingredients as appropriate to the desired preparation.

The active ingredient will be present in the compositions in aneffective amount to block histamine H₂ -receptors. The route ofadministration may be oral or parenteral.

Preferably, each dosage unit will contain the active ingredient in anamount of from about 50 mg to about 250 mg.

The active ingredient will preferably be administered one to six timesper day. The daily dosage regimen will preferably be from about 150 mgto about 1500 mg.

Advantageously the composition will be made up in a dosage formappropriate to the desired mode of administration, for example as atablet, capsule, injectable solution or as a cream or ointment fortopical application.

The invention is illustrated but in no way limited by the followingexamples, wherein all temperatures are in degrees Centigrade.

EXAMPLE 1 S-5-(N'-methylthioureido)pentyl]isothiouronium acetatemonohydrate

(i) Triethylamine (84 ml, 0.60 mole) was added dropwise over a period of6 hours to a stirred solution of1-methyl-2-thioxo-4,5-imidazolidinedione (88 g, 0.61 mole) and1,5-dibromopentane (264 g, 1.20 mole) in dimethylsulphoxide (650 ml) atroom temperature. The mixture was allowed to stand overnight and thenpoured into ice water (3 liters) containing concentrated hydrobromicacid (1 ml). The mixture was extracted with chloroform and the extractswere washed with water, dried over magnesium sulphate and evaporated togive an oil which was treated with hexane to give yellow crystals of1-(5-bromopentyl)-3-methyl-2-thioxo-4,5-imidazolidinedione (82.3 g),m.p. 48°-50°.

(ii) 1-(5-Bromopentyl)-3-methyl-2-thioxo-4,5-imidazolidinedione (81 g,0.276 mole) and thiourea (21 g, 0.276 mole) were heated together underreflux in acetone (450 ml) for 21 hours. On cooling in ice yellowcrystals ofS-[5-(1-(3-methyl-4,5-dioxo-2-thioxoimidazolidinyl))pentyl]isothioureahydrobromide (77.6 g) were obtained. A sample recrystallised frommethanol/ether had m.p. 169°-171°.

(Found: C, 32.6; H, 4.7; N, 15.4; S, 17.5; Br, 21.5% C₁₀ H₁₆ N₄ O₂.HBrrequires: C, 32.5; H, 4.6; N, 15.2; S, 17.4; Br, 21.6%)

(iii)S-[5-(1-(3-Methyl-4,5-dioxo-2-thioxoimidazolidyl))pentyl]isothioureahydrobromide (23 g) was dissolved in methanol (100 ml) and water (10 ml)and to this solution was added ammonium hydroxide (220 ml). The mixturewas allowed to stand for 10 min. and a further 50 ml of ammoniumhydroxide was added. After a further 5 min. the mixture was cooled indry ice/acetone and freeze dried at 0.005 mm Hg. The residue was takenup in water, acidified to pH 3 with hydrobromic acid and the insolublematerial filtered off. After extraction with ether to remove impuritiesthe aqueous solution was passed through an ion-exchange column(Amberlite IRA 400, acetate form) at 50° and the volume of the eluantreduced to approximately 150 ml. On standing overnight at 5° whitecrystals were obtained which were recrystallised from water containing alittle acetic acid to afford the title compound, m.p. 101°-104°.

(Found: C, 38.5; H, 7.8; N, 18.1; S, 20.5; C₈ H₁₈ N₄ S₂.CH₃ CO₂ H.H₂ Orequires: C, 38.4; H, 7.7; N, 17.9; S, 20.5%)

EXAMPLE 2 S-[6-(N'-Methylthioureido)hexyl]isothiouronium acetatemonohydrate

(i) When, the procedure of Example 1 (i) 1,6-dibromohexane was used inplace of 1,5-dibromopentane the product was1-(6-bromohexyl)-3-methyl-2-thioxo-4,5-imidazolidinedione, m.p. 63°-65°(from hexane).

(Found: C, 39.4; H, 4.9; N, 9.2; S, 10.2; Br, 26.2% C₁₀ H₁₅ Br N₂ O₂ Srequires: C, 39.1; H, 4.9; N, 9.1 S, 10.4; Br, 26.0%)

(ii) Reaction of1-(6-bromohexyl)-3-methyl-2-thioxo-4,5-imidazolidinedione and thioureaby the procedure of Example 1 (ii) and recrystallisation of the productfrom methanol/ether gaveS-[6-(1-(3-methyl-4,5-dioxo-2-thioxoimidazolidinyl))hexyl]-isothioureahydrobromide, m.p. 131°-133°.

(Found: C, 34.8; H, 5.0; N, 14.7; S, 16.5; C₁₁ H₁₈ N₄ O₂ S₂.HBrrequires: C, 34.5; H, 5.0; N, 14.6; S, 16.7%)

(iii) Alkaline hydrolysis ofS-[6-(1-(3-methyl-4,5-dioxo-2-thioxoimidazolidinyl))hexyl]isothioureausing the method described in Example 1 (iii) gave, afterrecrystallisation from water,S-[6-(N'-methylthioureido)hexyl]isothiouronium acetate monohydrate, m.p.105°-108°.

(Found: C, 40.3; H, 8.0; N, 17.0; S, 19.6; C₉ H₂₀ N₄ S₂.CH₃ CO₂ H.H₂ Orequires: C, 40.5; H, 8.0; N, 17.2; S, 19.6%)

EXAMPLE 3 S-[3-(N'-methylthioureido)propyl]isothiouronium acetate

By the procedure of Example 1(i), 1,3-dibromopropane was reacted with1-methyl-2-thioxo-4,5-imidazolidinedione to yield1-(3-bromopropyl)-3-methyl-2-thioxo-4,5-imidazolidinedione which, onreaction with thiourea by the procedure of Example 1(ii) gaveS-[6-(1-(3-methyl-4,5-dioxo-2-thioxoimidazolidinyl))propyl]isothioureahydrobromide. Hydrolysis of the latter compound by the procedure ofExample 1(iii) and recrystallisation of the product from water gave thetitle compound, m.p. 141°-143°.

(Found: C, 36.2; H, 6.8; N, 21.2; S, 23.8% C₆ H₁₄ N₄ S₂.CH₃ COOHrequires: C, 36.1; H, 6.8; N, 21.0; S, 24.1%)

EXAMPLE 4 S-[4-(N'-methylthioureido)butyl]isothiouronium hemisulphate

By the procedure of Example 1(i), 1,4-dibromobutane is reacted with1-methyl-2-thioxo-4,5-imidazolidinedione to yield1-(4-bromobutyl)-3-methyl-2-thioxo-4,5-imidazolidinedione which, onreaction with thiourea by the procedure of Example 1(ii) givesS-[4-(1-(3-methyl-4,5-dioxo-2-thioxoimidazolidinyl))butyl]isothioureahydrobromide, m.p. 113°-114°. Hydrolysis of the latter compound andworking up of the product by the general procedure of Example 1(iii) andconversion to the sulphate with ion-exchange resin (Amberlite IRA 400,sulphate form) gave the title product as a hygroscopic amorphous solid,m.p. 63°-65°.

EXAMPLE 5 S-(5-(N'-Cyano-N"-methylguanidino)pentyl)isothiouroniumacetate

(i) A mixture of 5-aminopentan-1-ol (20 g.) andN-cyano-N',S-dimethylisothiourea (25 g.) in pyridine (130 ml) was heatedon a steam-bath for 14 hours, evaporated to dryness, and the residuerecrystallised from chloroform/methanol to giveN-cyano-N'-(5-hydroxypentyl)-N"-methylguanidine (15.7 g). Arecrystallised sample had m.p. 116°-119°.

(Found: C, 51.9; H, 8.8; N, 30.3; C₈ H₁₆ N₄ O requires C, 52.2; H, 8.8;N, 30.4%)

(ii) A solution of p-toluenesulphonyl chloride (9.11 g) in pyridine (40ml) was added in portions to a stirred solution ofN-cyano-N'-(5-hydroxypentyl)-N"-methylguanidine (8.0 g) in pyridine (40ml) at -10°. The mixture was stirred at 2° for 40 hours and was pouredinto ice-water. The aqueous mixture was extracted with chloroform, andthe extracts were washed with dilute hydrochloric acid and evaporated togive 5-(N'-cyano-N"-methylguanidino)pentyl p-toluenesulphonate (6.3 g)as an orange oil.

(iii) A mixture of 5-(N'-cyano-N"-methylguanidino)pentylp-toluenesulphonate (6.3 g), thiourea (1.42 g) in acetone (50 ml) wasboiled under reflux for 18 hours. The acetone was decanted off and theresidual oil was dissolved in a small volume of water and passed down anion-exchange column (Amberlite 400, acetate form). Fractions containingthe required product were evaporated, and the residue recrystallisedfrom isopropanol to give the title product (2.1 g) m.p. 142°-144°.

EXAMPLE 6

Substitution of 6-aminohexan-1-ol for 5-aminopentan-1-ol in the generalprocedure of Example 5 leads to the production ofS-(6-(N'-cyano-N"-methylguanidino)hexyl)isothiourea.

EXAMPLE 7

Substitution of

(a) 3-aminopropan-1-ol

(b) 4-aminobutan-1-ol

for 5-aminopentan-1-ol in the general procedure of Example 5 leads tothe production of

(a) S-(3-(N'-cyano-N"-methylguanidino)propyl)isothiourea

(b) S-(4-(N'-cyano-N"-methylguanidino)butyl)isothiourea

EXAMPLE 8

A mixture of 6-aminohexan-1-ol and1-methylamino-1-methylthio-2-nitroethylene in ethanol is heated on asteam-bath to give 1-(6-hydroxyhexyl)-1-methylamino-2-nitroethylene.Substitution of 1-(6-hydroxyhexyl)-1-methylamino-2-nitroethylene forN-cyano-N'-(5-hydroxypentyl)-N"-methylguanidine in the procedure ofExample 5 (ii and iii) leads to the production ofS-[6-((1-methylamino-2-nitrovinyl)amino)hexyl]isothiourea.

EXAMPLE 9

Substitution of

(a) 3-aminopropan-1-ol

(b) 4-aminobutan-1-ol

(c) 5-aminopentan-1-ol

for 6-aminohexan-1-ol in the procedure of Example 8 leads to theproduction of

(a) S-[3-((1-methylamino-2-nitrovinyl)amino)propyl]isothiourea

(b) S-[4-((1-methylamino-2-nitrovinyl)amino)butyl]isothiourea

(c) S-[5-((1-methylamino-2-nitrovinyl)amino)pentyl]isothiourea

EXAMPLE 10

N-Butylthiourea is treated with oxalyl chloride to give1-butyl-2-thioxo-4,5-imidazolidinedione which when substituted for1-methyl-2-thioxo-4,5-imidazolidinedione in the procedure of Example 1gives S-[5-(N'-butylthioureido)pentyl]isothiourea.

EXAMPLE 11

Substitution of N-cyano-N'-butyl-S-methylisothiourea forN-cyano-N',S-dimethylisothiourea in the procedure of Example 5 givesS-(5-(N'-cyano-N"-butylguanidino)pentyl)isothiourea

EXAMPLE 12

Substitution of 1-butylamino-1-methylthio-2-nitroethylene for1-methylamino-1-methylthio-2-nitroethylene in the procedure of Example 8gives S-[6-((1-butylamino-2-nitrovinyl)amino)hexyl]isothiourea.

EXAMPLE 13

Treatment of 2-thioxo-4,5-imidazolidinedione with an excess of1,5-dibromopentane and triethylamine gives1,3-bis(5-bromopentyl)-2-thioxo-4,5-imidazolidinedione, which aftertreatment with an excess of thiourea and deprotection of the product bythe general procedure of Example 1(iii) givesN,N'-bis(5-(S-isothioureido)pentyl)thiourea.

EXAMPLE 14

Heating dimethyl N-cyanodithioimidocarbonate with an excess of5-aminopentan-1-ol in pyridine givesN-cyano-N',N"-bis(5-hydroxypentyl)guanidine, which may be treated withp-toluenesulphenyl chloride in pyridine and the product heated withthiourea in acetone to giveN-cyano-N',N"-bis(5-(S-isothioureido)pentyl)guanidine.

EXAMPLE 15

Heating 1-nitro-2,2-bis(methylthio)ethylene with an excess of5-aminopentan-1-ol in ethanol gives1,1-bis(5-hydroxypentyl)-2-nitroethylene, which may be treated withp-toluenesulphonyl chloride in pyridine and the product heated withthiourea in acetone to give1,1-bis(5-(S-isothioureido)pentyl)-2-nitroethylene.

EXAMPLE 16

Passage of aqueous solutions of

(a) S-[6-(N'-methylthioureido)hexyl]isothiouronium acetate

(b) S-[5-(N'-Cyano-N"-methylguanidino)pentyl]isothiouronium acetate

down an ion-exchange column (Amberlite IRA 400, sulphate form) andevaporation and crystallisation of the eluate gives

(a) S-[6-(N'-methylthioureido)hexyl]isothiouronium hemisulphate

(b) S-[5-(N'-cyano-N"-methylguanidino)pentyl]isothiouronium hemisulphate

and use of Amberlite IRA 400, hydrochloride form gives

(a) S-[6-(N'-methylthioureido)hexyl]isothiourea hydrochloride

S-[5-(N'-cyano-N"-methylguanidino)pentyl]isothiourea hydrochloride.

EXAMPLE 17 Pharmaceutical Composition

    ______________________________________                                        Ingredients              Amounts                                              ______________________________________                                        S-[6-(N'-methylthioureido)hexyl]-                                             isothiouronium hemisulphate                                                                            100 mg                                               Sucrose                  50 mg                                                Starch                   15 mg                                                Talc                     4 mg                                                 Stearic Acid             2 mg                                                 ______________________________________                                    

The ingredients are screened, mixed and filled into a hard gelatincapsule.

EXAMPLE 18 Pharmaceutical Composition

    ______________________________________                                        Ingredients              Amounts                                              ______________________________________                                        S-[6-(N'-methylthioureido)hexyl]-                                             isothiouronium hemisulphate                                                                            125 mg                                               Lactose                  75 mg                                                ______________________________________                                    

The ingredients are screened, mixed and filled into a hard gelatincapsule.

Similarly, the other compounds of Formula 1 may be formulated intopharmaceutical compositions by the procedures of Examples 17 and 18.

The pharmaceutical compositions prepared as in the foregoing examplesare administered to a subject within the dose ranges given hereabove toblock histamine H₂ -receptors and to alleviate inflammation.

What is claimed is:
 1. A compound of the formula ##STR8## wherein n isan integer from 3 to 6; R is lower alkyl .[.or.]. ##STR9## X is sulphur;or a pharmaceutically acceptable acid addition salt thereof.
 2. Acompound of claim 1 wherein n is 5 or
 6. 3. A compound of claim 1, saidcompound being a salt of S-[6-(N'-methylthioureido)hexyl]isothiourea. 4.A compound of claim 1, said compound being a salt ofS-[5-(N'-methylthioureido)pentyl]isothiourea.
 5. A compound of claim 1which is in the form of a pharmaceutically acceptable acid additionsalt.
 6. A pharmaceutical composition.Iadd., in the form of a tablet,capsule or sterile injectable liquid, .Iaddend.to block histamine H₂-receptors comprising in an effective amount to block said receptors acompound of .[.claim 1.]. .Iadd.the formula: ##STR10##.Iaddend. whereinn is an integer from 3 to 6; R is lower alkyl or ##STR11## and X issulphur in the form of a pharmaceutically acceptable acid addition saltin combination with a pharmaceutically acceptable diluent or carrier. 7.A pharmaceutical composition of claim 6 in unit dosage form for oraladministration.
 8. A method of blocking histamine H₂ -receptors whichcomprises administering to an animal in need thereof in an effectiveamount to block said receptors a compound of .[.claim 1.]. .Iadd.theformula: ##STR12##.Iaddend. and X is sulphur; or a pharmaceuticallyacceptable acid addition salt thereof.
 9. A method of treatinginflammation which comprises administering to an animal in need thereofin an effective amount to treat inflammation a compound of .[.claim 1.]..Iadd.the formula: ##STR13##.Iaddend. wherein n is an integer from 3 to6; R is lower alkyl or ##STR14## and X is sulphur; or a pharmaceuticallyacceptable acid addition salt thereof.